JP2005512598A - Eiavなどのレンチウイルス発現ベクターを使用するトランスジェニック生物の作製方法 - Google Patents
Eiavなどのレンチウイルス発現ベクターを使用するトランスジェニック生物の作製方法 Download PDFInfo
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Abstract
Description
(a)アプタザイムをコードする第2核酸配列、及び
(b)ポリヌクレオチドを生成することができる第3核酸配列を含み、
(a)及び(b)は機能できる形で結合し、且つ前記ポリヌクレオチドが生じるように第1核酸配列の転写物を切断すべくアプタザイムを活性化することができるベクターが提供される。
(c)アプタザイムをコードする第1核酸配列、及び
(d)ポリヌクレオチドを生成することができる第2核酸配列を含み、
(a)及び(b)は機能できる形で結合し、前記ポリヌクレオチドが生じるように核酸配列の転写物を切断すべくアプタザイムを活性化することができる核酸配列を含むベクターの提供である。
(a)アプタザイムをコードする第2核酸配列、及び
(b)NOIを含む第3核酸配列を含み、
(a)及び(b)は機能できる形で結合し、且つ前記NOIの発現が阻害されるように第1核酸配列の転写物を切断すべくアプタザイムを活性化することができるベクターが提供される。
(c)アプタザイムをコードする第1核酸配列、及び
(d)NOIを含む第2核酸配列を含み、
(a)及び(b)は機能できる形で結合し、且つ前記NOIの発現が阻害されるように核酸配列の転写物を切断すべくアプタザイムを活性化することができる。
癌に関係する遺伝子には、それだけには限らないが、Cdh3、Ncam、Akp2、Asgr2、Bax、Bmp4、Ccnd1、Cd38、Cdc37、Cdkn1a、Cdkn1b、Cdkn1c、Csk、Epas1、Fgf2、Grpr、HBV、Igf1、Inhbb、Inpp5d、IRS1、Itga5、Kcna1、lacZ、Map2k4、Mdm2、Nfkbia、Ngfb、Oxt、Pemt、Plp、Shh、Src、Stat5a、Tcfap2a、Trp53、Blmh、Cd152、Cmkar2、Cmkbr5、Csf1、Csf3、Egfr、Gzmb、Ifng、Ifngr、IGFBP3、Il1r1、Il1rap、Il2、Il2ra、1l2rb、Il2rg、Il4、Il4ra、Il5、Il6、Il7r、Il10、Il12a、Il12b、Il12rb1、Il12rb2、IRSl、Kdr、Lifr、Lta、Ncam、Ntf3、Ntf5、Ntrk1、Ntrk2、Ntrk3、Ph、prlr、Scya3、Smst、Tgfa、Tgfb1、Tgfb2、Tgfb3、Tnf、Tnfrsf1a、Tnfrsf1b、Tnfrsf5、Apc、Prkdc、TAg、Amh、Kit、Kitl、Ter、Fech、hr、Atm、E2f1、Hoxl1、Apc、Cdh3、Erbb2、Hras、Met、Notch4、PIP、PyVT、Tag、Wnt1、Madh3、Nf1、Ptch、Rb1、Odc、Bcl3、Fos、Fyn、Jun、Kras2、luc、Mos、Myc、Rab3a、Rela、Yes、Cd44、Mgmt、Plg、Ahr、Pgy2、Rag1、Btk、Igh−6、.Jak3、Tcra、Tcrb、Tcrd、Ttp53、Ttpa、Vhlh、及びWt1が含まれる。
ベクターの調製
先に述べた通り、293Tヒト胚腎細胞の一過性同時形質移入によってベクターを調製した(Mitrophanous等、1999)。EIAVベクターゲノムSMART2Zは、内部CMVプロモーターからβ−ガラクトシダーゼレポーター遺伝子を発現する。それはEIAVのセントラルポリプリントラクト(cPPT)(Stetor等、1999)及びウッドチャック肝炎転写後調節エレメント(WPRE)(Donello等、1998)を含む。
以下のように胎仔血管内に注射することによってベクターを投与した。イソフルラン麻酔下で最深(full depth)正中開腹を実施して妊娠16日目の妊娠マウスの子宮を露出させた。各胎仔に2×107T.U.(形質転換単位)のベクターを総容量20μlで34ゲージ針(Hamilton)を使用して末梢卵黄嚢血管中に投与した。母1頭につき5頭までの胎仔に注入した。層と層を縫合することによって開腹を閉じ、保温ケージ中にマウス放置して回復させた。
受胎後18〜19日目に仔が生まれた。イソフルラン麻酔で安楽死させることによってマウスを様々な生成段階(注射後3、7、14、28、及び79日目)で屠殺し、組織像のための試料を調製した。臓器を100%エタノール溶液中に2時間置いた後、ベクターによって発現したβ−ガラクトシダーゼ標識遺伝子をX−gal溶液で(lmg/mlの5−ブロモ−4−クロロ−3−インドリル−β−D−ガラクトピラノシドを含むジメチルスルホキシド液、5mMのフェリシアン化カリウム、5mMのフェロシアン化カリウム、2mMの塩化マグネシウム)で染色した。染色した組織を10%ホルムアルデヒド中で2時間固定し、パラフィン包埋し、切片を作り、ニュートラルレッドで対比染色した。染色によって肝臓、肺、心臓、筋肉、腎臓、骨格筋、及び脳を含む幾つかの臓器の形質導入が示された。結果を図1〜11に示す。
この実施例は、実施例1の方法に続いて実施する。血友病は、不可欠な凝固因子が部分的には又は完全に失われている血液状態である。X連鎖性劣性障害である。血友病には2つの型があり、最も一般的なものは因子VIIIを欠く血友病Aである。血友病Bでは、因子IXが欠けている。EIAVを使用して、EIAVによって因子VIII又はIXを血友病胎仔の臍静脈、又は周産期胎仔の肝臓門脈に送達する。
本出願人同時係属GB0202403.1に記載されているものなどのベクター。より詳しくは:
pONY8.4シリーズのベクターは、力価に有害な作用を及ぼすことなく、アクセサリータンパク質に全く依存しない一過性又は安定したベクター系の一部としてこれを機能させることを可能にする幾つかの修飾を受けている。従来、レンチウイルスベクターゲノムは、適切な力価を得るために(一過性又は安定)産生細胞中にウイルスタンパク質revの存在を必要としてきた。これには、現在のHIVベクター系及び初期EIAVベクターが含まれる。
a)gagに由来しパッケージングシグナルの一部を形成するATGモチーフ全てをATTGを読み取るために修飾した。これによりLTR中のプロモーターによって作動され得るオープンリーディングフレームの挿入が可能となる。
以下のようにPCRを実施した:
産物A=プライマーKM001+KM003、標的としてpONY8.1Zと共に。
因子VIII(野生種完全長オープンリーディングフレーム(ORF)、又は野生種ORFで欠失させた切断B領域、又はコドン最適化ORF、又はコドン最適化ORFで欠失させた切断B領域)を発現する(上記のものなどの)EIAVウイルスベクターを実施例1の方法に続き、静脈内、肝臓内、又は筋肉内送達を含めて投与した。CMVなどの適当なプロモーター、又はPGKなどのヒトプロモーター/エンハンサーを使用して遺伝子を発現させる。さらに、Tet系などの誘導性プロモーターを発現を調節するために使用することができる。代替法として組織特異的プロモーター/エンハンサーを細胞型に合わせて発現を制限するために使用することができる。
因子IX(野生種ORF又はコドン最適化ORF、)を発現する(上記のものなどの)EIAVウイルスベクターを実施例1の方法に続き、静脈内、肝臓内、又は筋肉内送達を含めて投与した。CMVなどの適当なプロモーター、又はPGKなどのヒトプロモーター/エンハンサーを使用して遺伝子を発現させる。さらに、Tet系などの誘導性プロモーターを発現を調節するために使用することができる。代替法として組織特異的プロモーター/エンハンサーを細胞型に合わせて発現を制限するために使用することができる。
この実施例を実施例1の方法に続き実施する。嚢胞性線維症は、イオン輸送、粘液流体力学、炎症、及び細菌付着に役割を有すると考えられているタンパク質である嚢胞性線維症膜コンダクタンス制御因子(CFTR)の突然変異が原因の劣性遺伝障害である。EIAVを使用して肺の形質導入のためにCFTRを羊水へ送達する。
この実施例を実施例1の方法に続き実施する。デュシェンヌ型筋ジストロフィ(DMD)は、致死性X連鎖性劣性障害である。DMDは、横紋筋系中のタンパク質ジストロフィンの濃度及び/又は活性の遺伝的欠損から生じる。EIAVを使用して(軽度のベッカー型筋ジストロフィ(BMD)の表現型に対応する)ミニジストロフィンcDNAを周産期胎仔の臍静脈に、及び/又は直接胎仔骨格筋に送達する。
この実施例を実施例1の方法に続き実施する。メラニンを生成する生合成経路上の遺伝子を標的にするリボザイムをEIAVを使用して送達する。この手法によってトランスジェニック体の同定が容易になる。
パーキンソン病(PD)は、65歳を超える人口の約2%が罹患している最も一般的な神経変性疾患の1つである。この疾患は、その症状が強剛性、安静時振戦、及び運動緩慢(動作の開始、実行が緩慢)である運動障害パーキンソン病の症状を特徴とする。これは、神経伝達物質ドーパミンを生成する黒質中のニューロンの消失から生じる。この疾患が受け継がれる数種の稀有なファミリーがあるが、PDの原因は大部分不明である。常染色体優性PDを有するファミリーにおいて、2つの異なるミスセンスの突然変異が、α−シヌクレイン中にマップされているが(Polymeropoulos等、1997;Kruger等、1998)、このα−シヌクレインはシナプス小胞の輸送に関与すると考えられる小さいリンタンパク質である。青年期に発症する常染色体劣性若年性パーキンソン病(AR−JP)では、Kitadaら(1998)がパーキン(parkin)を担う遺伝子、E3ユビキチンリガーゼを示した。このリガーゼは最近α−シヌクレインのユビキチン化に触媒作用を及ぼすことが提案された(Shimura等、2001)。したがって、α−シヌクレインを分解できるかどうかが、AR−JP及びおそらく散発性PD(Haass及びKahle,2001)を招くことが示唆されてきた。
2.突然変種α−シヌクレイン対立遺伝子
3.リボザイムをチロシンヒドロキシラーゼへ(ドーパミン合成に必要な酵素)
低酸素誘導因子(HIF)は、酸素の恒常性において中心的役割を担う転写複合体である。HIF中のヒドロキシル化プロリン残基を認識するフォンヒッペルリンドウユビキチン化複合体によって、標準条件下でHIFのαサブユニットは分解を標的としている。結果として安定状態のタンパク質濃度は低く、転写複合体は生じることができない。その酵素活性が低酸素、鉄キレート化、及びコバルトイオンによって調節されるプロリル−4−ヒドロキシラーゼのファミリーが最近記載されており、HIFを調節する酸素センサであるための要件を満たしている(Epstein等、2001)。キイロショウジョウバエ(Drosophila melanogaster)の細胞培養物中でRNA干渉によってプロリル−4−ヒドロキシラーゼが抑制されると、標準条件下で低酸素誘導遺伝子の高い発現がもたらされた(Bruick and McKnight,2001)。
1.リボザイムをプロリル−4−ヒドロキシラーゼ(又はVHL)へ。これは、HIF−lαサブユニットの構成的上方調節、HIF複合体の活性化、及びHIF標的遺伝子の過剰発現をもたらすことができる。
図20は、幾つかのRNAi用発現カセットを例示し、このカセットをレンチウイルス、例えば、EIAV中に使用してトランスジェニック細胞及び動物中でsiRNAを発現させることができる。これらの個々の実施例では、RNAポリメラーゼIIIプロモーター(U6)が使用されている。RNAポリメラーゼIIIは、小さい5SリボソームRNA及び転移RNAを含む様々の非常に小さく安定したRNAを生成する。効率的なRNAiは、単一U6プロモーター(図20A)由来の短いヘアピンの発現、又は一方がセンス領域を発現し、他方が標的と同じ配列の相補鎖(reverse complement)を発現する2つのU6プロモーターに組み込む(図20B)ことによって媒介される。図20Cに示す実施形態では、2つの対向するプロモーターを使用して前及び発現カセットの相補鎖から標的のセンス及びアンチセンス領域を転写する。
トランスジェニック動物を作製するためにウイルスベクター、例えばレンチウイルスベクターを使用して、重要な又は不可欠な機能を有する遺伝子産物を標的とするsiRNAを送達することは、作製中にトランスジェニック動物に死をもたらし得る。siRNAの転写を調節し、それによってサイレンシング効果を調節可能にする能力は大変望まれているはずである。この実施例では、本発明者らは、機能性siRNAの生成調節にアプタマー/リボザイムハイブリッド(「アプタザイム」)の使用を述べる。
この実施例では、本発明者らは、機能性siRNAの生成を調節するための「アプタザイム」の使用について説明し、そこではアプタマーに特異的なタンパク質リガンドが同じベクターから発現する。ベクターを図22に例示したように構築する。RNAポリメラーゼIII U6snRNA遺伝子プロモーターを使用して、VEGFに対してアプタザイムに結合した短いヘアピンの発現を作動する。低酸素条件下で低酸素応答エレメント(HRE)からの発現が誘発され、アプタマーのリガンドであるタンパク質Xをコードする遺伝子Xを転写する。アプタザイムへのリガンドの結合は、触媒作用、短いヘアピン放出、結果として血管内皮細胞増殖因子(VEGF)の遺伝子サイレンシングを誘発する。
この実施例では、本発明者らは、RNAポリメラーゼIIプロモーターの制御下でのsiRNA前駆体の転写について説明する。これは、短いヘアピン(図23A)、又はsiRNA配列(図23B)の両脇にアプタザイムなどの触媒RNAをコードする、又はその標的である配列を置くことによって達成される。フランキング配列の切断によって前駆体からsiRNA又は短いヘアピンが放出される。
遺伝子を含むいかなる核酸配列の転写後調節にもアプタザイムを使用することができる。転写物の一部、例えばイニシエーターであるメチオニンのコドンを除去して、又はUTRがキャッピング及び/又は転写物のポリアデニル化を防止して、転写物の切断を誘発する適当なリガンド付加/除去によりアプタザイムは活性化(又は阻害)される。これは、濃度が高過ぎる場合、遺伝子産物、例えば、因子IXなどの治療用遺伝子の合成を停止する手段を提供する。このようにして導入遺伝子の発現を自己調節的であるように設計することもできる。
アプタザイム活性を最小化、したがって自己切断によるベクターゲノムの不要な崩壊を最小にするはずの条件下で本発明のウイルスベクターの作製を実施すべきであるが、好ましい手段はベクターを分割イントロンベクターとして構成することによりアプタザイム(又はリボザイム)を物理的に分離することである(Ismail等、2000)。これによってリボザイムの全配列が、プロウイルスによってコードされている転写物中にしか存在せず、ベクター粒子中に存在するRNAゲノムには存在しないことを確実になる。
Claims (65)
- 所望のヌクレオチド(NOI)を含む非霊長類レンチウイルス発現ベクターを細胞に導入するステップを含むトランスジェニック細胞の作製方法。
- 前記NOIが、治療用タンパク質又はアプタザイムをコードし、且つ発現することができる、或いはアンチセンスオリゴヌクレオチド、リボザイム、siRNA、短いヘアピンRNA、マイクロRNA、又はグループIイントロンを生成することができる請求項1に記載の方法。
- 前記非霊長類レンチウイルス発現ベクターが、EIAV、FIV、BIV、CAEV、又はMVVに由来する請求項1又は2に記載の方法。
- NOI又はアプタザイムを含むレンチウイルス発現ベクターを細胞に導入するステップを含み、アンチセンスオリゴヌクレオチド、リボザイム、siRNA、短いヘアピンRNA、マイクロRNA、又はグループIイントロンを生成することができるトランスジェニック細胞の作製方法。
- 前記レンチウイルス発現ベクターが、EIAV、FIV、BIV、CAEV、MVV、又はHIVに由来する請求項4に記載の方法。
- 前記発現ベクターを生体内(in vivo)又は生体外(ex vivo)で導入する請求項1から5のいずれか記載の方法。
- 前記細胞が、子宮内細胞である請求項6に記載の方法。
- 前記細胞が、周産期細胞である請求項7に記載の方法。
- 前記細胞が、胚細胞である請求項8に記載の方法。
- 前記細胞が、胎児細胞である請求項9に記載の方法。
- 前記細胞が、生殖細胞系列の変化を生じさせることができる請求項1から10のいずれか記載の方法。
- 前記細胞が、生殖細胞である請求項11に記載の方法。
- 前記細胞が、配偶子形成に関与する請求項11に記載の方法。
- 前記細胞が、卵母細胞、卵管細胞、卵巣細胞、卵子、卵原細胞、接合体、ES細胞、胚盤細胞、精母細胞、精細胞、精子、又は精原細胞である請求項11から13のいずれか記載の方法。
- 前記レンチウイルス発現ベクターを胚盤葉、臍帯、胎盤、羊水、子宮、又は生殖腺を介して、或いは腹腔内、筋肉内、脊髄内、頭蓋内、静脈内、呼吸器内、胃腸、又は肝内投与によって前記細胞に導入する請求項1から14のいずれか記載の方法。
- 前記レンチウイルス発現ベクターを胚盤葉、臍帯、胎盤、又は羊水を介して、或いは腹腔内、筋肉内、脊髄内、頭蓋内、静脈内、呼吸器内、胃腸、又は肝内投与によって子宮内細胞に導入する請求項15に記載の方法。
- NOIを含むレンチウイルス発現ベクターを非分裂細胞に導入するステップを含むトランスジェニック細胞の作製方法。
- 前記レンチウイルス発現ベクターが、EIAV、FIV、BIV、CAEV、MVV、又はHIVに由来する請求項17に記載の方法。
- 前記NOIが、タンパク質又はアプタザイムをコードし、且つ発現することができる、或いはアンチセンスオリゴヌクレオチド、リボザイム、siRNA、短いヘアピンRNA、マイクロRNA、又はグループIイントロンを生成することができる請求項17又は18に記載の方法。
- 前記細胞が、生殖細胞系列の変化を生じさせることができる請求項17から19のいずれか記載の方法。
- 前記細胞が、生殖細胞である請求項20に記載の方法。
- 前記細胞が、配偶子形成に関与する請求項20に記載の方法。
- 前記細胞が、卵母細胞である請求項22に記載の方法。
- 前記細胞が、動物又は酵母に由来する請求項1から23のいずれか記載の方法。
- 前記細胞が、非ヒト生物に由来する請求項24に記載の方法。
- 前記細胞が、哺乳動物細胞である請求項24に記載の方法。
- 前記細胞が、マウス、ヒト、ブタ、ウシ、サル、ヒツジ、ウマ、鳥類、昆虫、爬虫類、又は魚類の細胞である請求項24に記載の方法。
- 前記細胞が、線虫(C.elegans)又はキイロショウジョウバエに由来する請求項24に記載の方法。
- 前記レンチウイルス発現ベクターが偽型である請求項1から28のいずれか記載の方法。
- 前記レンチウイルス発現ベクターがいかなる機能性アクセサリー遺伝子も含まない請求項1から29のいずれか記載の方法。
- NOIが、構成的プロモーター、組織特異的プロモーター、又は誘導性プロモーターに機能できる形で結合されている請求項1から30のいずれか記載の方法。
- 請求項1から31のいずれか記載の方法によって作製したトランスジェニック細胞。
- 請求項32に記載のトランスジェニック細胞から、又は請求項1から31のいずれか一項で定義した方法から生成することによって生じる、又は得ることができるトランスジェニック生物。
- 前記NOIが、卵管細胞、生殖路細胞、(単球、マクロファージ、リンパ球、顆粒球、又はこれらのいずれかの前駆細胞を含む)造血細胞、分泌細胞、乳腺細胞、内皮細胞、腫瘍細胞、間質細胞、星状膠細胞、又はグリア細胞、筋細胞、上皮細胞、ニューロン、線維芽細胞、肝細胞、腎臓細胞、肝臓細胞、心臓細胞、又は肺細胞中に発現される請求項33に記載のトランスジェニック生物。
- 前記生物が、鳥類である請求項33又は34に記載のトランスジェニック生物。
- 前記生物が、ニワトリ、アヒル、又はガチョウなどの家禽である請求項35に記載のトランスジェニック生物。
- 請求項33から36のいずれか記載のトランスジェニック生物由来のトランスジェニック卵。
- タンパク質をコードし、且つ発現することができる少なくとも1個のNOIを含む請求項のいずれか記載のトランスジェニック生物又は卵。
- さらに、アプタザイム、アンチセンスオリゴヌクレオチド、リボザイム、siRNA、短いヘアピンRNA、マイクロRNA、又はグループIイントロンを生成することができる少なくとも1個のNOIを含む請求項38に記載のトランスジェニック生物又は卵。
- 第1核酸配列を含むベクターであって、前記第1核酸配列が
(a)アプタザイムをコードする第2核酸配列、及び
(b)ポリヌクレオチドを生成することができる第3核酸配列を含み、
(a)及び(b)は機能できる形で結合し、且つ前記ポリヌクレオチドが生じるように前記第1核酸配列の転写物を切断すべく前記アプタザイムを活性化することができるベクター。 - 前記ポリヌクレオチドが、標的遺伝子の発現を調節することができるRNA分子である請求項40に記載のベクター。
- 前記RNA分子が、アプタザイム、siRNA、短いヘアピンRNA、マイクロRNA、アンチセンスRNA及びリボザイムからなる群から選択される請求項41に記載のベクター。
- 第1核酸配列を含むベクターであって、前記第1核酸配列が
(a)アプタザイムをコードする第2核酸配列、及び
(b)NOIを含む第3核酸配列を含み、
(a)及び(b)は機能できる形で結合し、且つ前記NOIの発現が阻害されるように第1核酸配列の転写物を切断すべく前記アプタザイムを活性化することができるベクター。 - 前記第3核酸配列の転写物内の位置で前記第1核酸配列の転写物を切断すべく前記アプタザイムを活性化することができる請求項43に記載のベクター。
- NOIが、治療用タンパク質をコードする請求項43又は44に記載のベクター。
- 前記アプタザイムが、リガンドによって活性化される請求項40から45のいずれか記載のベクター。
- 前記アプタザイムが、リガンドによって不活化される請求項40から45のいずれか記載のベクター。
- 前記ベクターが、請求項46又は47のリガンドをコードする第4核酸配列を含む請求項46又は47に記載のベクター。
- 前記リガンドをコードする前記核酸配列がプロモーターに機能できる形で結合されている請求項48に記載のベクター。
- 前記リガンドが、ポリペプチド及びその断片、線状ペプチド、環状ペプチド、及びそれらをコードする核酸、低分子量の有機又は無機の化合物及び抗体を含む、合成及び天然化合物からなる群から選択される請求項46から49に記載のベクター。
- 前記リガンドが、FMN、ドキシサイクリン及びVEGF、テトラサイクリン及びグルコースからなる群から選択される請求項46から49に記載のベクター。
- (a)及び(b)が、プロモーターに機能できる形で結合されている請求項40から51のいずれか記載のベクター。
- 前記プロモーターが、RNAポリメラーゼIIIプロモーター及びRNAポリメラーゼIIプロモーターからなる群から選択される請求項52に記載のベクター。
- 前記第1核酸配列の転写がテトラサイクリンモジュレータ及びテトラサイクリン又はその誘導体によって調節されるように、前記プロモーターが少なくとも1コピーのテトラサイクリン応答因子(TRE)に機能できる形で結合されている請求項52に記載のベクター。
- 前記ベクターがテトラサイクリンモジュレータをコードする第5核酸配列を含む請求項54に記載のベクター。
- 前記ウイルスRNAゲノム内でヘアピンを形成して活性アプタザイムが形成されることを防止するために、前記アプタザイムの部分と塩基対を作りうる配列を前記プロモーターがその3’末端に含む請求項52から55のいずれか記載のベクター。
- ウイルスベクターの形である請求項40から56のいずれか記載のベクター。
- ウイルスRNAゲノム内に活性アプタザイムが形成されることを防止するために、前記ベクターが分割イントロンベクターとして構成されている請求項57に記載のベクター。
- 前記ベクター系が、レトロウイルス、レンチウイルス、アデノウイルス、アデノ随伴ベクター、ヘルペスベクター、ポックスウイルスベクター、パルボウイルスベクター、及びバキュロウイルスベクターに由来する請求項57又は58に記載のベクター。
- 請求項40から59のいずれか記載のベクターを使用するトランスジェニック細胞の作製方法。
- 請求項60で定義したトランスジェニック細胞から生成することによって生じる、又は得ることができるトランスジェニック生物。
- 請求項46から59のいずれか記載のウイルスベクターを使用する請求項1から31のいずれか記載の方法。
- 請求項62に記載の方法によって作製したトランスジェニック細胞。
- 請求項63に記載のトランスジェニック細胞から生成することによって生じる、又は得ることができるトランスジェニック生物。
- NOIが、卵管細胞、生殖路細胞、アルブミン、(単球、マクロファージ、リンパ球、顆粒球、又はこれらのいずれかの前駆細胞を含む)造血細胞、分泌細胞、乳腺細胞、内皮細胞、腫瘍細胞、間質細胞、又はグリア細胞、筋細胞、上皮細胞、ニューロン、線維芽細胞、肝細胞、星状膠細胞、腎臓細胞、肝臓細胞、心臓細胞、又は肺細胞中に発現される請求項64に記載のトランスジェニック生物。
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GBGB0211409.8A GB0211409D0 (en) | 2001-12-21 | 2002-05-17 | Transgenic organism |
PCT/GB2002/005901 WO2003056022A2 (en) | 2001-12-21 | 2002-12-23 | Method for producing a transgenic organism using a lentiviral expression vector such as eiav |
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WO2023196818A1 (en) | 2022-04-04 | 2023-10-12 | The Regents Of The University Of California | Genetic complementation compositions and methods |
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CN1322137C (zh) * | 1997-12-22 | 2007-06-20 | 牛津生物医学(英国)有限公司 | 基于马传染性贫血病毒(eiav)的逆转录病毒载体 |
GB0227645D0 (en) * | 2002-11-27 | 2003-01-08 | Viragen Inc | Protein production in transgenic avians |
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2002
- 2002-12-23 CN CN02828287.6A patent/CN1620508A/zh active Pending
- 2002-12-23 EP EP02788249A patent/EP1458879A2/en not_active Withdrawn
- 2002-12-23 AU AU2002353231A patent/AU2002353231B2/en not_active Ceased
- 2002-12-23 JP JP2003556539A patent/JP2005512598A/ja active Pending
- 2002-12-23 WO PCT/GB2002/005901 patent/WO2003056022A2/en active Application Filing
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2003
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2008
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Cited By (3)
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JP2006512062A (ja) * | 2002-11-27 | 2006-04-13 | ビラーゲン・インコーポレーテッド | トランスジェニック鳥類におけるタンパク質産生 |
JP2008541734A (ja) * | 2005-05-30 | 2008-11-27 | コモンウェルス サイエンティフィック アンド インダストリアル リサーチ オーガニゼイション | 基底膜粒子の製造及び使用 |
JP2012147791A (ja) * | 2009-01-06 | 2012-08-09 | Functional Genetics Inc | 熱非対称インターレース(tail)pcrを用いたランダムホモ接合性遺伝子摂動(rhgp) |
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US20040040052A1 (en) | 2004-02-26 |
US20090007284A1 (en) | 2009-01-01 |
WO2003056022A3 (en) | 2003-12-31 |
AU2002353231A1 (en) | 2003-07-15 |
WO2003056022B1 (en) | 2004-02-12 |
WO2003056022A2 (en) | 2003-07-10 |
EP1458879A2 (en) | 2004-09-22 |
AU2002353231B2 (en) | 2008-10-16 |
CN1620508A (zh) | 2005-05-25 |
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